Phase 0 Analysis of Ixazomib (MLN9708) in Patients With Glioblastoma

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02630030
• Collaborator: Takeda (Industry)
• Enrollment: 3
• Location: 1
• Arm: 1
• Actual Duration (Months): 53.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase 0 trial studies ixazomib citrate in treating patients with glioblastoma that has spread or returned after period of improvement who are planning to undergo surgery. When given by mouth, ixazomib may be able to reach tumor cells in the brain. Studying samples of tissue, blood, and plasma in the laboratory from patients receiving ixazomib may help doctors learn more about the effects of ixazomib on the cells. It may also help doctors understand how well patients will respond to treatment.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	Drug: Ixazomib	Early Phase 1

Detailed Description

PRIMARY OBJECTIVES:

1. Measurement of tissue concentration of ixazomib (ixazomib citrate) in a glioblastoma after preoperative administration.

2. Measurement of blood and plasma concentration of ixazomib during surgical sampling after preoperative administration.

SECONDARY OBJECTIVE:

1. Assessment of the safety of ixazomib after single dose administration in glioblastoma patients undergoing surgery for tissue concentration assessment.

OUTLINE:

Patients receive ixazomib orally (PO) 3 hours before surgery.

After completion of study, patients are followed up for 30 days and then periodically thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Phase 0 Analysis of Ixazomib (MLN9708) in Patients With Glioblastoma
• Actual Study Start Date: Mar 24, 2016
• Actual Primary Completion Date: Jul 1, 2018
• Actual Study Completion Date: Sep 3, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ixazomib Patients receive ixazomib PO 3 hours before surgery.	Drug: Ixazomib; Given PO; Other Names: MLN9708

Outcome Measures

Primary Outcome Measures

1. Concentration of Ixazomib in Tumor Tissue [At time of surgery, approximately 3 hours]

   The relationship between patient's demographic, tumor and drug concentration results will be assessed with Pearson's correlation coefficient and tested with Wald's test. In addition, the mean and standard error of the concentrations will be estimated using a random-effects model to account for the within-patient correlation of the tumor biopsy samples. Given the limited number of observations, a relatively simple covariance matrix (e.g. compound symmetry) will be assumed.

2. Number of Patients With Safety and Tolerability of Ixazomib [At the time of surgery, approximately 3 hours]

   Safety was assessed with routine postoperative laboratory, vital sign, neurologic exam, and imaging studies through the day of surgery to staple or suture removal. This data was collected and any adverse events graded and their relationship to ixazomib administration determined.

Secondary Outcome Measures

1. Number of Participants With Treatment-Emergent Adverse Events [Up to 30 days]

   The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE) was used to stratify any adverse patient response to ixazomib. There were no clinically relevant adverse events as a result of ixazomib administration.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

• Female patients who:

• Are postmenopausal for at least 1 year before the screening visit, OR

• Are surgically sterile, OR

• If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR

• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)

• Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

• Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR

• Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception)

• Patients must have a previous diagnosis of a recurrent or progressive glioblastoma for which surgical resection is now indicated

• Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2 or (Karnofsky performance status of 60 or above)

• Absolute neutrophil count (ANC) ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³; platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment

• Hemoglobin > 9 g/dL

• Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN for the lab utilized

• Creatinine ≤ 1.5 mg/dL

• Calculated creatinine clearance ≥ 30 mL/min

Exclusion Criteria:

• Female patients who are lactating or have a positive serum pregnancy test during the screening period

• Failure to have fully recovered (ie, ≤ grade 1 toxicity) from the reversible effects of prior chemotherapy

• Major surgery, including craniotomy, within 14 days before enrollment

• Radiotherapy of brain tumor within 3 months before enrollment

• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment

• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months

• Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors of cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family 3, subfamily A (CYP3A) (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of ginkgo biloba or St. John's wort

• Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive

• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol

• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent

• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing

• Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease; patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection

• Patient has ≥ grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period

• Participation in other clinical trials utilizing other therapeutic investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial

• Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University
• Takeda

Investigators

• Principal Investigator: Jeffrey J. Olson, MD, Emory University/Winship Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 23, 2015

More Information

Additional Information:

• Molecular and Clinical Oncology Publication

Publications

None provided.

• Responsible Party: Jeffrey James Olson, Principal Investigator, Emory University
• ClinicalTrials.gov Identifier: NCT02630030
• Other Study ID Numbers: IRB00083003; NCI-2015-01682; X16071; Winship3017-15
• First Posted: Dec 15, 2015
• Last Update Posted: Mar 26, 2021
• Last Verified: Feb 1, 2021

• Additional relevant MeSH terms: Glioblastoma; Ixazomib

Study Results

Participant Flow

Arm/Group Title	Ixazomib
Arm/Group Description	Patients receive ixazomib PO 3 hours before surgery. Ixazomib: Given PO
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Ixazomib
Arm/Group Description	Patients receive ixazomib PO 3 hours before surgery. Ixazomib: Given PO
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 66.7%
>=65 years	1 33.3%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.33 (NA)
Sex: Female, Male (Count of Participants)
Female	1 33.3%
Male	2 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 33.3%
White	2 66.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Concentration of Ixazomib in Tumor Tissue
Description	The relationship between patient's demographic, tumor and drug concentration results will be assessed with Pearson's correlation coefficient and tested with Wald's test. In addition, the mean and standard error of the concentrations will be estimated using a random-effects model to account for the within-patient correlation of the tumor biopsy samples. Given the limited number of observations, a relatively simple covariance matrix (e.g. compound symmetry) will be assumed.
Time Frame	At time of surgery, approximately 3 hours

Outcome Measure Data

Analysis Population Description

Each participant's sample was analyzed separately. For participant 3, 3 samples were collected and analyzed in order to account for intratumor variability

Arm/Group Title	Ixazomib
Arm/Group Description	Patients receive ixazomib PO 3 hours before surgery. Ixazomib: Given PO
Measure Participants	3
Participant 1	7.88
Participant 2	2.03
Participant 3 Sample 1	4.17
Participant 3 Sample 2	2.70
Participant 3 Sample 3	3.25

2. Primary Outcome

Title	Concentration of Ixazomib in Tumor Tissue
Description	The relationship between patient's demographic, tumor and drug concentration results will be assessed with Pearson's correlation coefficient and tested with Wald's test. In addition, the mean and standard error of the concentrations will be estimated using a random-effects model to account for the within-patient correlation of the tumor biopsy samples. Given the limited number of observations, a relatively simple covariance matrix (e.g. compound symmetry) will be assumed.
Time Frame	At time of surgery, approximately 3 hours

Outcome Measure Data

Analysis Population Description

Each participant's plasma concentration was analyzed separately.

Arm/Group Title	Ixazomib
Arm/Group Description	Patients receive ixazomib PO 3 hours before surgery. Ixazomib: Given PO
Measure Participants	3
Participant 1	21.8
Participant 2	18.0
Participant 3	36.2

3. Primary Outcome

Title	Number of Patients With Safety and Tolerability of Ixazomib
Description	Safety was assessed with routine postoperative laboratory, vital sign, neurologic exam, and imaging studies through the day of surgery to staple or suture removal. This data was collected and any adverse events graded and their relationship to ixazomib administration determined.
Time Frame	At the time of surgery, approximately 3 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixazomib
Arm/Group Description	Patients receive ixazomib PO 3 hours before surgery. Ixazomib: Given PO
Measure Participants	3
Count of Participants [Participants]	3 100%

4. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events
Description	The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE) was used to stratify any adverse patient response to ixazomib. There were no clinically relevant adverse events as a result of ixazomib administration.
Time Frame	Up to 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ixazomib
Arm/Group Description	Patients receive ixazomib PO 3 hours before surgery. Ixazomib: Given PO
Measure Participants	3
Count of Participants [Participants]	3 100%

Adverse Events

Time Frame	Adverse events collected through study completion, 30 days after study drug administration.
Arm/Group Title	Ixazomib
Arm/Group Description	Patients receive ixazomib PO 3 hours before surgery. Ixazomib: Given PO
All Cause Mortality
	Ixazomib
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Ixazomib
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Other (Not Including Serious) Adverse Events
	Ixazomib
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Anemia	2/3 (66.7%)
General disorders
Lipase	1/3 (33.3%)
Confusion	2/3 (66.7%)
Immune system disorders
Thrombocytopenia	1/3 (33.3%)
Renal and urinary disorders
Proteinuria	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Dysarthria	1/3 (33.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.